rs587782958

chr11-47333552-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_Strong PP5_Very_Strong

The NM_000256.3(MYBPC3):c.3190+5G>A variant causes a splice donor 5th base, intron change. The variant allele was found at a frequency of 0.00000622 in 1,447,474 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 splice_donor_5th_base, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:18
• Conservation: PhyloP100: 4.92

Genes affected

MYBPC3 (HGNC:7551): (myosin binding protein C3) MYBPC3 encodes the cardiac isoform of myosin-binding protein C. Myosin-binding protein C is a myosin-associated protein found in the cross-bridge-bearing zone (C region) of A bands in striated muscle. MYBPC3 is expressed exclusively in heart muscle and is a key regulator of cardiac contraction. Mutations in this gene are a frequent cause of familial hypertrophic cardiomyopathy. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-47333552-C-T is Pathogenic according to our data. Variant chr11-47333552-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 155808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47333552-C-T is described in Lovd as [Pathogenic]. Variant chr11-47333552-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.3190+5G>A		splice_donor_5th_base_variant, intron_variant		ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.3190+5G>A		splice_donor_5th_base_variant, intron_variant		5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.3190+5G>A		splice_donor_5th_base_variant, intron_variant		5		A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000168 AC: 4 AN: 238780 Hom.: 0 AF XY: 0.0000230 AC XY: 3 AN XY: 130308

Gnomad AFR exome AF: 0.0000650

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000622 AC: 9 AN: 1447474 Hom.: 0 Cov.: 32 AF XY: 0.00000833 AC XY: 6 AN XY: 720484

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Feb 17, 2012	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. MYBPC3 IVS29+5 G>A Given the type of variant, the case data, the in vitro data, and the absence in general population samples we consider this variant likely disease causing. The variant has been seen in at least 10 unrelated cases of HCM. There is weak segregation data from two families. Rodriguez-Garcia et al (2010) reported the variant in one of 20 individuals from their Spanish cohort. It segregated with disease in two affected first degree relatives. In an abstract from the 2005 HUGO meeting, an Australian group reported that they observed the variant in an individual with HCM in a cohort of 150 individuals that had DHLPC-based analysis of MYH7 and MYBPC3 (Yu et al 2005). Ancestry was not reported. Crehalet et al (2012) observed the variant in a patient with HCM from their French cohort of 280 HCM patients. Rodriguez-Garcia et al (2010) note that bionformatics analysis predicted an impact on splicing (programs used were reported as SSF, ASSP, NetGene2, HSF). The nucleotide at the +5 position of the consensus splice junction sequence. Crehalet et al (2012) note that 3 of 5 splicing algorithms they used predicted aberrant splicing. They assessed impact on splicing using a mini-gene assay and found that exon 29 was completely skipped and the resulting transcript include a premature stop codon and would likely be subject to nonsense-mediated decay. Splicing and other protein-truncating variants in MYBPC3 are a frequent cause of HCM (Erdmann et al. 2001 & 2003; Stenson et al 2003; Harvard Sarcomere Protein Gene Mutation Database). Many MYBPC3 splice variants have been reported in association with HCM including IVS2-1G>A, IVS6-2A>C IVS7+1G>A, IVS8+1G>A, IVS12-2A>G, IVS14-2A>G, IVS16-1G>A, IVS22+1G>A, IVS24+1G>A, IVS28+1G>A, IVS32+1G>A, and IVS33+1G>A (Harvard Sarcomere Protein Gene Mutation Database). Furthermore, these types of variants in MYBPC3 are not seen in individuals without cardiomyopathy (Pan et al 2012). In total the variant has not been seen in ~6700 published controls and individuals from publicly available population datasets. The variant is not listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of June 5th, 2014). There are no variants at the splice donor site in intron 29 listed in that dataset. It is listed in the 1000 genomes browser, but this appears to point to the HGMD listing and an online database that appears to be connected to Yu et al. The variant was not observed in the following published control samples: 200 controls (Rodriguez-Garcia et al 2010). -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 11, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 11, 2022	Not observed at a significant frequency in large population cohorts (gnomAD); Functional studies demonstrated that c.3190+5 G>A results in skipping of exon 29, which would encode a truncated protein or result in absent protein via nonsense-mediated decay (Crehalet et al., 2012); Intronic +5 splice site variant in a gene for which loss-of-function is a known mechanism of disease, and splice predictors support a deleterious effect; This variant is associated with the following publications: (PMID: 23283745, 2943217, 31028938, 30847666, 33190526, 20800588, 25351510, 19574547, 30645170, 31006259, 30775854, 33673806, 20433692, 28679633) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2018	- -

Hypertrophic cardiomyopathy 4 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Region Ostergotland	Jul 02, 2020	PS4, PP3, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Intron variant: previously reported to alter splicing and result in a loss of normal protein fucnction through nonsense-mediated decay (NMD) or protein truncation (. https://doi.org/10.4081/cardiogenetics.2012.e6. . . Predicted Consequence/Location:). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000155808 / 3billion dataset). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Hypertrophic cardiomyopathy Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 23, 2023	This sequence change falls in intron 29 of the MYBPC3 gene. It does not directly change the encoded amino acid sequence of the MYBPC3 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs587782958, gnomAD 0.007%). This variant has been observed in individuals with clinical features of hypertrophic cardiomyopathy (PMID: 20433692, 20800588, 30645170, 30775854). ClinVar contains an entry for this variant (Variation ID: 155808). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (http://dx.doi.org/10.4081/cardiogenetics.2012.e6). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 08, 2024	This variant (also known as IVS29+5G>A) causes a G to A nucleotide substitution at the +5 position of intron 29 of the MYBPC3 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Functional RNA studies have reported conflicting results: In a minigene assay, this variant has been shown to alter mRNA splicing by causing exon 29 skipping, which is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay (PMID: 28679633; Crehalet et al., 2012, https://doi.org/10.4081/cardiogenetics.2012.e6). Another study using the RNA sample derived from a carrier individual's peripheral blood cells has shown no abnormal splicing (PMID: 30645170), however, authors did not comment on the possibility of RNA degradation in their assay. This variant has been reported in more than 20 unrelated individuals affected with hypertrophic cardiomyopathy from various populations (PMID: 20433692, 20800588, 23283745, 25351510, 28138913, 28615295, 28679633, 30775854, 31028938, Crehalet et al., 2012, Burns, 2019). It has been shown that this variant segregates with disease in multiple individuals across 4 families (PMID: 20433692, 30645170; communication with an external laboratory; ClinVar SCV000203979.6). This variant has been identified in 4/238780 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 27, 2021	The c.3190+5G>A variant in MYBPC3 has been identified in at least 15 individuals with hypertrophic cardiomyopathy (HCM) and segregated with disease in 8 affected relatives from 3 families (Rodríguez-García 2010 PMID: 20433692, Crehalet 2012, Zou 2013 PMID: 23283745, Lopes 2015 PMID: 25351510, Singer 2019 PMID: 30645170, Jaaskelainen 2019 PMID: 30775854, ClinVar SCV000188790.4, LMM data). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID# 155808) and has also been identified in 0.002% (2/112442) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). The c.3190+5G>A variant is located in the 5' splice region. Computational tools predict an impact on splicing and in vitro functional studies involving cell-based minigene assays have shown that this variant caused exon 29 skipping, resulting in a truncated protein (Crehalet 2012, Ito 2017 PMID: 28679633). However, studies using patient RNA from fresh blood were unable to corroborate these findings (Singer 2019 PMID: 30645170). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PP1_Strong, PS4_Strong, PM2_Supporting, PP3. -

Cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 23, 2023	This variant (also known as IVS29+5G>A) causes a G to A nucleotide substitution at the +5 position of intron 29 of the MYBPC3 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Functional RNA studies have reported conflicting results: In a minigene assay, this variant has been shown to alter mRNA splicing by causing exon 29 skipping, which is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay (PMID: 28679633; Crehalet et al., 2012, https://doi.org/10.4081/cardiogenetics.2012.e6). Another study using the RNA sample derived from a carrier individual's peripheral blood cells has shown no abnormal splicing (PMID: 30645170), however, authors did not comment on the possibility of RNA degradation in their assay. This variant has been reported in more than 20 unrelated individuals affected with hypertrophic cardiomyopathy from various populations (PMID: 20433692, 20800588, 23283745, 25351510, 28138913, 28615295, 28679633, 30775854, 31028938, Crehalet et al., 2012, Burns, 2019). It has been shown that this variant segregates with disease in multiple individuals across 4 families (PMID: 20433692, 30645170; communication with an external laboratory; ClinVar SCV000203979.6). This variant has been identified in 4/238780 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jan 03, 2023	- -

Primary familial hypertrophic cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Dec 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 29, 2024	Variant summary: MYBPC3 c.3190+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a canonical 5' splicing donor site. One predicts the variant weakens this site. At least one publication reports experimental evidence that this variant affects mRNA splicing, leading to exon 29 skipping (Crehalet_2012). The variant allele was found at a frequency of 1.7e-05 in 238780 control chromosomes (gnomAD). c.3190+5G>A has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy (Crehalet_2012, Rodrguez-Garca_2010, Zou_2013). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 20433692, 23283745). ClinVar contains an entry for this variant (Variation ID: 155808). Based on the evidence outlined above, the variant was classified as pathogenic. -

Hypertrophic cardiomyopathy;C0013404:Dyspnea;C0018794:Heart block;C0039231:Tachycardia;C0151636:Premature ventricular contraction;C0205700:Asymmetric septal hypertrophy;C1839832:Noncompaction cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 03, 2022

The c.3190+5G>A intronic pathogenic mutation results from a G to A substitution 5 nucleotides after coding exon 29 in the MYBPC3 gene. This alteration has been reported in unrelated individuals with hypertrophic cardiomyopathy and, in one study, was identified in a proband, the proband's affected daughter, and the proband's unaffected daughter (Millat G et al Clin Chim Acta. 2010 Dec; 411(23-24):1983-91; Rodríguez-García MI et al. BMC Med Genet. 2010; 11():67; Zou Y et al. Mol Biol Rep. 2013 Jun; 40(6):3969-76). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. By in vitro studies, this alteration was revealed to cause exon 29 skipping, which is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay (Crehalet H et al. Cardiogenetics. 2012 May; 2:e6; Ito K et al. Proc. Natl. Acad. Sci. U.S.A., 2017 07;114:7689-7694). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
Cadd	Benign	22
Dann	Benign	0.61

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.85		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.85		Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587782958; hg19: chr11-47355103;